a-Synuclein Aggregation Intermediates form Fibril Polymorphs with Distinct Prion-like Properties

alpha-Synuclein (alpha-Syn) amyloids in synucleinopathies are suggested to be structurally and functionally diverse, reminiscent of prion-like strains. The mechanism of how the aggregation of the same precursor protein results in the formation of fibril polymorphs remains elusive. Here, we demonstrate the structure- function relationship of two polymorphs, pre-matured fibrils (PMFs) and helix-matured fibrils (HMFs), based on alpha-Syn aggregation intermediates. These polymorphs display the structural differences as demonstrated by solid-state NMR and mass spectrometry studies and also possess different cellular activities such as seeding, internalization, and cell-to-cell transfer of aggregates. HMFs, with a compact core structure, exhibit low seeding potency but readily internalize and transfer from one cell to another. The less structured PMFs lack transcellular transfer ability but induce abundant alpha-Syn pathology and trigger the formation of aggresomes in cells. Overall, the study highlights that the conformational heterogeneity in the aggregation pathway may lead to fibril polymorphs with distinct prion-like behavior.(c) 2022 Elsevier Ltd. All rights reserved.

Automated summary

This study demonstrates the structure-function relationship of two polymorphs (PMFs and HMFs) based on alpha-Syn aggregation intermediates. These polymorphs show distinct structural differences and cellular activities, which have important implications for the occurrence and propagation of synucleinopathies.